Abstract
Amidinobenzimidazole derivatives connected to 1-aryl-substituted 1,2,3-triazole through phenoxymethylene linkers 7a–7e, 8a–8e, and 9a–9e were designed and synthesised with the aim of evaluating their anti-bacterial and anti-trypanosomal activities and DNA/RNA binding affinity. Results from anti-bacterial evaluations of antibiotic-resistant pathogenic bacteria revealed that both o-chlorophenyl-1,2,3-triazole and N-isopropylamidine moieties in 8c led to strong inhibitory activity against resistant Gram-positive bacteria, particularly the MRSA strain. Furthermore, the non-substituted amidine and phenyl ring in 7a induced a marked anti-bacterial effect, with potency against ESBL-producing Gram-negative E. coli better than those of the antibiotics ceftazidime and ciprofloxacin. UV–Vis and CD spectroscopy, as well as thermal denaturation assays, indicated that compounds 7a and 8c showed also binding affinities towards ctDNA. Anti-trypanosomal evaluations showed that the p-methoxyphenyl-1,2,3-triazole moiety in 7b and 9b enhanced inhibitory activity against T. brucei, with 8b being more potent than nifurtimox, and having minimal toxicity towards mammalian cells.
Highlights
The benzimidazole derivatives, which contain fused heterocyclic nuclei within their structures, are structural isosteres of purine bases
1,2,3-Triazole-linked 5-amidinobenzimidazoles 7a–7e, 8a–8e, and 9a–9e are synthesised as outlined in Scheme 1. 4Hydroxybenzaldehyde was propargylated to give 4-(prop-2-ynyloxy)benzaldehyde (2), which subsequently via the regioselective Cu(I) catalysed cycloaddition with aromatic azides resulted in 4–(1,2,3-triazol-1-yl)benzaldehyde derivatives (3a–3e) comprising an N-1-aryl-substituted 1,2,3-triazole subunit
Amidino-substituted 1,2-phenylenediamines (4–6) that were used for the synthesis of the target 5-amidinobenzimidazoles 7a–7e, 8a–8e, and 9a–9e were synthesised from the corresponding nitrile by the Pinner method58. 4-Amidino 1,2-phenylenediamines (4–6) reacted with the bisulfite adduct of the 4–(1,2,3triazol-1-yl)benzaldehyde derivatives (3aÀe) to produce amidine (7a–7e), N-isopropylamidine (8a–8e), and imidazoline-substituted (9a–9e) benzimidazole derivatives[69]
Summary
The benzimidazole derivatives, which contain fused heterocyclic nuclei within their structures, are structural isosteres of purine bases. This allows them to interact with biopolymers and they, have diverse biological and clinical applications[1,2,3,4,5]. Much research effort has been aimed at targeting DNA with benzimidazole ligands, with the goal of designing agents that have therapeutic applications[5,6,7,8,9]. RNA is a well-established target of current antibiotics, designing new compounds that selectively recognise RNA has been a difficult task, when focused on the treatment of a variety of infections[10,11,12]. While there are many areas of therapy that might benefit from DNAdirected intervention, there is currently an urgent need for new antimicrobials with novel modes of action
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